Proteins of the Wnt family function in a variety of inductive signaling events, control cell polarity, determine cell fate and promote cell proliferation (Nusse et al. (1992) Cell 69:1073-1087; McMahon (1992) Trends Genet. 8:236-242). The first known wnt gene, Drosophila wingless (wg) gene, was identified genetically by a weak mutation that disrupts formation of the wing of adult flies (Sharma et al. (1976) Dev. Biol. 48:461-464) and it was later found that null mutations in wingless result in patterning defects and embryonic lethality (Nüsslein-Volhard et al. (1980) Nature 287:795-801). Wg protein is required for patterning of the Drosophila embryo and development of muscle, midgut, neuron and imaginal disc. In C. elegans, these genes are required for generation of cell polarity and cell fate determination. In vertebrates, Wnt proteins are required for body axis formation and proper development of brain, kidney and many other organs (Cadigan et al. (1997) Genes Dev. 11:3286-3305).
Through biochemical and genetic studies, several components of the Wnt signaling pathway have been identified. Much attention has focused on the role of the β-catenin/Armadillo protein which, in response to Wnt/Wg, becomes stabilized, moves to the nucleus and forms complex with the LEF1/TCF transcription factors to regulate gene expression. The level of cytosolic β-catenin is determined by its interaction with a number of proteins including those in a multiprotein complex of Axin, glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and other proteins (Polakis (1999) Curr. Opin. Genet. Dev. 9:15-21). The mechanism by which the Wnt signal is transmitted to the Axin/GSK-3β/APC complex is unclear but it involves interaction of Wnt with its receptors, which are members of Frizzled (Frz) family of seven transmembrane proteins. When Wnt is activated by binding of Wnt to the Frz family of receptors, the Dsh protein is hyperphosphorylated and recruited to the membrane area. Activated Dsh inhibits GSK-3β action, which normally phosphorylates β-catenin and directs it, together with APC and axin family members to degradation by the ubiquitin-proteosome system. Decreased degradation of β-catenin leads to its accumulation, nuclear translocation, and association with LEF1/TCF. Ben-Ze'ev and Geiger (1998) Curr. Opin. Cell Biol. 10:629-639.
Disregulation of the Wnt/Wg pathway and accumulation of β-catenin is associated with a variety of cancers. For example, in colon and other cancers, mutations in APC or presumptive GSK-3β phosphorylation sites of β-catenin are associated with constitutive activation of LEF1/TCF transcription. Sparks et al. (1998) Cancer Res. 58:1130-1134; and Kolligs et al. (1999) Mol. Cell. Biol. 19:5696-5706. Constitutive activation of LEF1 was shown to induce oncogenic transformation of chicken embryo fibroblasts. Aoki et al. (1999) Proc. Natl. Acad. Sci. USA 96:139-144. Accumulation of β-catenin is associated with intestinal tumors. Crawford et al. (1999) Oncogene 18:2883-2891. Regulation of β-catenin stability is also thought to play a major role in melanomas, breast cancer, neuroblastoma, ovarian carcinomas, medulloblastomas, and other tumors. Aberle et al. (1996) Proc. Natl. Acad. Sci. USA 92:6384-6388; Rubinfeld et al. (1997) Science 275:1790-1792; Zurawel et al. (1998) Cancer Res. 58:896-899; Palacios and Gamallo (1998) Cancer Res. 58:1344-1347; Mai et al. (1999) Genomics 55:341-344. β-catenin may act as an oncogene by excessively activating gene(s) that directly contribute to tumor progression.
There exists a need in the art for an understanding of the cellular pathways involved in control of cell proliferation. There further exists a need for ways of regulating uncontrolled cell proliferation. The present invention addresses these needs and provides additional advantages as well.